tbuckley/cabot-search huggingface dataset:
Abstract LB526: HBI-2375, a selective inhibitor of MLL1-WDR5 interaction, possesses desirable preclinical characteristics to be pursued in IND enabling studies and future clinical investigations
Authors: Farbod Shojaei, J E. Semple, Che Fang, Jill M. Ricono, Fairooz Kabbinavar, Bob Goodenow, Mireille Gillings
Journal: Cancer Research (2022)

Abstract 92130MLL1 (mixed lineage leukemia1) interaction with WDR5 (WD repeat domain 5) is critical for MLL1 histone methyl transferase (H3K4me) activity leading to transcriptional regulation of gene expression. MLL1 dysregulation such as its translocation at chromosome 11q23 results in generation of MLL1 fusion genes and leukemia development. Additionally, recent studies indicated a role for MLL1-WDR5 interaction in solid tumors progression via directly affecting cancer cells or by suppression of tumor immunity. Therefore, MLL1-WDR5 interaction is an important target in cancer drug discovery, both in leukemia and in solid tumors. HUYABIO recently completed acquisition of a novel series of MLL1-WDR5 inhibitors and conducted an additional SAR campaign to identify a lead compound with greater efficacy and PK (pharmacokinetics)characteristics. Characterization of a series of analogs identified HBI-2375 as a selective inhibitor of MLL1-WDR5 interaction. TR-FRET peptide binding assay indicated potent binding of HBI-2375 to WDR5 (IC50=4.48 nM) and in vitro cell potency studies showed inhibition of proliferation in MV4;11 leukemia cells by HBI-2375 (IC50=3.17 µM).Furthermore, HBI-2375 was stable in liver S9 and whole blood and displayed reasonable PK properties (Cmax, T1/2, AUC and F%) in preclinical testing in mouse and dog. In vivo efficacy studies in MV4;11 model showed 86% and 77% tumor growth inhibition in HBI-2375 treated tumors when dosed at 80 mpk or 40 mpk (po, qd x 21) respectively. In addition, HBI-2375 was found to be well tolerated since body weight data in the recipients did not show a significant change throughout the treatment. Interestingly, ex vivo tumor analysis showed a reduction in H3K4me in both 40 and 80 mpk samples, further validating target-driven activity of HBI-2375. These data resulted in the nomination of HBI-2375 as the lead clinical candidate for the current IND enabling studies and future investigations in the clinic. Citation Format: Farbod Shojaei, J E. Semple, Che Fang, Jill M. Ricono, Fairooz Kabbinavar, Bob Goodenow, Mireille Gillings. HBI-2375, a selective inhibitor of MLL1-WDR5 interaction, possesses desirable preclinical characteristics to be pursued in IND enabling studies and future clinical investigations [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr LB526.
Abstract 2603: USP1 inhibitor synthetic lethality in BRCA1-mutant cancer is driven by PCNA ubiquitination
Authors: Justin Engel, Madhavi Bandi, Antione Simoneau, Katherine Lazarides, Deepali Gotur, Truc Pham, Shangtao Liu, Samuel Meier, Ashley Choi, Hongxiang Zhang, Binzhang Shen, Fang Li, Douglas Whittington, Shanzhong Gong, Xuewen Pan, Yi Yu, Lina Gu, Scott Throner, John Maxwell, Yingnan Chen, Alan Huang, Jannik Andersen, Tianshu Feng
Journal: Cancer Research (2022)

Abstract CRISPR-based functional genomic screening is a powerful approach for identifying novel classes of synthetic lethal drug targets. Here, we define the deubiquitinase USP1 as a synthetic lethal target in cancers with underlying DNA repair vulnerabilities. A highly potent and selective small molecule USP1 inhibitor conferred a viability defect in BRCA1-mutant, but not WT cell lines by activating replication stress. Genome-wide CRISPR screening uncovered RAD18 and UBE2K, which promote PCNA mono- and poly-ubiquitination respectively, as key mediators of USP1-BRCA1 dependency. Increased cellular mono- and poly-ubiquitination reduced PCNA protein levels, and restoration of PCNA protein expression rescued USP1 inhibitor sensitivity. USP1 dependency is associated with upregulated RAD18 and UBE2K expression, suggesting that elevated PCNA ubiquitination in the context of BRCA1 deficiency mediates USP1 synthetic lethality. Interestingly, USP1, but not PARP1 inhibition, elicited a viability defect in a subset of BRCA1/2 WT lung cancer cell lines, indicative of novel synthetic lethal interactions unique to USP1. Moreover, dual inhibition of PARP1 and USP1 are strongly synergistic in PARP1 inhibitor-responsive cell line models. Strong in vivo anti-tumor activity across multiple tumor models was demonstrated with USP1 inhibition alone and in combination with the PARP1 inhibitor olaparib. Our studies suggest that USP1 and PARP1 inhibitors target BRCA1-mutant cancer though distinct yet synergistic mechanisms. As such, USP1 inhibitors may provide novel treatment strategies for PARP1 inhibitor-resistant and -naïve BRCA1-mutant cancer. Citation Format: Justin Engel, Madhavi Bandi, Antione Simoneau, Katherine Lazarides, Deepali Gotur, Truc Pham, Shangtao Liu, Samuel Meier, Ashley Choi, Hongxiang Zhang, Binzhang Shen, Fang Li, Douglas Whittington, Shanzhong Gong, Xuewen Pan, Yi Yu, Lina Gu, Scott Throner, John Maxwell, Yingnan Chen, Alan Huang, Jannik Andersen, Tianshu Feng. USP1 inhibitor synthetic lethality in BRCA1-mutant cancer is driven by PCNA ubiquitination [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2603.
Final Overall Survival Analysis of Gemcitabine and Cisplatin Induction Chemotherapy in Nasopharyngeal Carcinoma: A Multicenter, Randomized Phase III Trial
Authors: Yuan Zhang, Lei Chen, Guo-Qing Hu, Ning Zhang, Xiao-Dong Zhu, Kun-Yu Yang, Feng Jin, Mei Shi, Yu-Pei Chen, Wei-Han Hu, Zhi-Bin Cheng, Si-Yang Wang, Ye Tian, Xi-Cheng Wang, Yan Sun, Jin-Gao Li, Wen-Fei Li, Yu-Hong Li, Yan-Ping Mao, Guan-Qun Zhou, Rui Sun, Xu Liu, Rui Guo, Guo-Xian Long, Shao-Qiang Liang, Ling Li, Jing Huang, Jin-Hua Long, Jian Zang, Qiao-Dan Liu, Li Zou, Qiong-Fei Su, Bao-Min Zheng, Yun Xiao, Ying Guo, Fei Han, Hao-Yuan Mo, Jia-Wei Lv, Xiao-Jing Du, Cheng Xu, Na Liu, Ying-Qin Li, Fang-Yun Xie, Ying Sun, Jun Ma, Ling-Long Tang
Journal: Journal of Clinical Oncology (2022)

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically on the based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.We previously reported significantly improved failure-free survival using gemcitabine plus cisplatin induction chemotherapy in locoregionally advanced nasopharyngeal carcinoma. Here, we present the final overall survival (OS) analysis. In this multicenter, randomized trial, patients were assigned to be treated with concurrent chemoradiotherapy alone (standard therapy, n = 238) or gemcitabine and cisplatin induction chemotherapy before concurrent chemoradiotherapy (n = 242). With a median follow-up of 69.8 months, the induction chemotherapy group had a significantly higher 5-year OS (87.9% v 78.8%, hazard ratio, 0.51 [95% CI 0.34 to 0.78]; P = .001) and a comparable risk of late toxicities (≥ grade 3, 11.3% v 11.4%). Notably, the depth of the tumor response to induction chemotherapy correlated significantly and positively with survival (complete response v partial response v stable/progressive disease, 5-year OS, 100% v 88.4% v 61.5%, P = .005). Besides, patients with a low pretreatment cell-free Epstein-Barr virus DNA load (< 4,000 copies/mL) might not benefit from induction chemotherapy (5-year OS, 90.6% v 91.4%, P = .77). In conclusion, induction chemotherapy before concurrent chemoradiotherapy improved OS significantly in patients with locally advanced nasopharyngeal carcinoma, without increasing the risk of late toxicities. Tumor response to induction chemotherapy and pretreatment cell-free Epstein-Barr virus DNA might be useful to guide individualized treatment.
Abstract 6296: Preclinical evaluation of a panel of FGFR inhibitors for their normal brain and brain tumor distribution
Authors: William Knight, Kamal Shaik, Tigran Margaryan, Shwetal Mehta, Nader Sanai, Artak Tovmasyan
Journal: Cancer Research (2022)

Abstract Glioblastoma (GBM) is the most prevalent and lethal primary intrinsic brain tumor in adults with approximately 5-8% of GBM patients displaying fibroblast growth factor receptor (FGFR) gene mutations. This subset of GBM patients could potentially benefit from targeted FGFR inhibitor treatment, thus making it imperative to explore FGFR inhibitors as a therapeutic option. In this study, seven pan-FGFR inhibitors (infigratinib, AZD4547, debio1347, erdafitinib, LY2874455, pemigatinib, and TAS-120) were evaluated for their brain penetration ability employing cassette dosing strategy with an aim to identify the optimal candidates for brain tumor targeting. Cassette-dosing strategy was confirmed to be an acceptable approach for screening the panel of FGFR inhibitors by comparing pharmacokinetic parameters obtained from discrete- vs cassette-dosing studies. Subsequently, cassette-dosing strategy was utilized to investigate distributional kinetics of FGFR inhibitors in normal brain and brain tumor in wild-type and triple-knockout (Mdr1a/b-/-Bcrp1-/-) mice. The comparison of brain-to-plasma partition coefficients for total (Kp,brain) and unbound (Kp,brain) drug levels in wild-type and triple-knockout mice revealed the importance of major blood-brain barrier (BBB) efflux transporters in four out of seven FGFR inhibitors. The impact of BBB and efflux transporters were further evaluated in flank and orthotopic patient-derived xenograft mouse models of brain tumors. All FGFR inhibitors were shown to accumulate significantly in both flank and orthotopic brain tumors relative to normal brain. Furthermore, the levels in flank brain tumors were at least 10-fold higher as compared to the levels in orthotopic brain tumors with five FGFR inhibitors, indicating the critical role of efflux transporters and the impact of BBB disruption in the brain and brain tumor distribution. The predictive parameters of brain penetration calculated based on physico-chemical properties have been estimated and shown not to correlate with the experimentally obtained neuro-pharmacokinetic values. In summary, our study provides comprehensive evaluation of neuro-pharmacokinetic behavior of seven FGFR inhibitors and delivers rationale for selection of most optimal candidates for future investigation in brain tumor clinical trials. Citation Format: William Knight, Kamal Shaik, Tigran Margaryan, Shwetal Mehta, Nader Sanai, Artak Tovmasyan. Preclinical evaluation of a panel of FGFR inhibitors for their normal brain and brain tumor distribution [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6296.
Abstract 1074: Cellular uptake and metabolism of MT1-MMP-activated taxane prodrugs
Authors: Athina Polykandritou, Alexandra Serre, Hannah Spencer, Goreti R. Morais, Amanda Race, Steven Shnyder, Paul Loadman, Robert A. Falconer
Journal: Cancer Research (2022)

Abstract ICT3205 is a targeted cytotoxic agent, comprised of an MT1-MMP-specific peptide and a paclitaxel warhead. Paclitaxel, originally approved in 1992, is one of the most commonly used chemotherapies for various cancer types, but is often characterized by its dose-limiting toxicity and low aqueous solubility. Tumor-targeted prodrugs are a promising strategy for the selective delivery of taxanes to prostate tumors, especially given the results of STAMPEDE trial1. Previous work has shown that ICT3205 is selectively metabolized in tumor tissue over the normal tissue, and that this is specifically mediated by MT1-MMP2. In vivo studies have demonstrated that when administered at an equimolar dose to paclitaxel, ICT3205 has a superior anticancer effect, with an absence of systemic toxicity. In this study we aim to further investigate the cellular uptake and metabolism of ICT3205 and other taxane analogues in MT1-MMP +ve (HT1080) and MT1-MMP -ve (MCF-7) cells in vitro. The compound will be also studied in the PC3 prostate cancer cell line, since it has been demonstrated before that there is a good correlation between MT1-MMP protein and mRNA expression. ICT3205 and analogues have been synthesized, and purified by semi-preparative HPLC. We report the tumor-specific metabolism of ICT3205 in prostate tumors ex vivo, and we are currently studying its cellular uptake and metabolism in MT1-MMP +ve and MT1-MMP -ve cancer cell-lines using HPLC, mass spectrometry and immunofluorescent microscopy. Moreover, ex vivo metabolism studies are performed on the analogues, while they will be also assessed for their metabolism and cellular uptake. These data will provide a better understanding of the mechanism of uptake and metabolism of this type of peptide prodrugs, and will provide the basis for the future synthesis and optimization of these prodrugs. 1.James ND et al. Addition of docetaxel, zoledronic acid, or both to first-line long-term hormone therapy in prostate cancer (STAMPEDE): survival results from an adaptive, multiarm, multistage, platform randomized controlled trial. Lancet. 2016;387(10024):1163-772.Loadman PM et al. Improved delivery of paclitaxel to prostate tumors: a membrane-type matrix metalloproteinase (MT-MMP)-targeted approach. Cancer Res. 2016;76:3 Citation Format: Athina Polykandritou, Alexandra Serre, Hannah Spencer, Goreti R. Morais, Amanda Race, Steven Shnyder, Paul Loadman, Robert A. Falconer. Cellular uptake and metabolism of MT1-MMP-activated taxane prodrugs [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1074.
Abstract LB022: A hybrid epithelial to mesenchymal transition in ex-vivo cutaneous squamous cell carcinoma tissues
Authors: Christopher S. Pulford, Chandana K. Uppalapati, McKale R. Montgomery, Elizabeth E. Hull, Kathryn J. Leyva
Journal: Cancer Research (2022)

Abstract While most cases of cutaneous squamous cell carcinoma (cSCC) are benign, invasive cSCC is associated with higher mortality and is often more difficult to treat. As such, understanding the factors that influence the progression of cSCC are important. Aggressive cancers metastasize through a series of evolutionary changes, collectively called the epithelial-to-mesenchymal transition (EMT). During EMT, epithelial cells transition to a highly mobile mesenchymal cell type with metastatic capacities. While changes in expression of TGF-β, vimentin, and E-cadherin are hallmarks, EMT is not an “all or none” process. Using patient-derived cSCC and adjacent normal tissues (ANT), we observed a significant increase in mRNA expression of TGF-β (p&amp;lt;0.05), TGF-βR2 (p&amp;lt;0.001), and E-cadherin (p&amp;lt;0.005) in cSCC tissues by qPCR. Immunoblots performed on homogenized tissues yielded significant and parallel increases in protein expression of TGF-β (p&amp;lt;0.05) and E-cadherin (p&amp;lt;0.05). We also observed increased expression of the EMT-associated transcription factors Zeb1 and Snai1 in cSCC tissue sections using immunohistochemistry. Interestingly, we observed a significant increase in expression of vimentin (p&amp;lt;0.01) by immunoblot and differential expression of four oncogenic and EMT-associated miRNAs; miR-31 expression was significantly higher in cSCC tissues (p&amp;lt;0.001), while we observed a significant decrease in expression of miR-34a (p&amp;lt;0.05), miR-200b, and miR-200c in cSCC tissues. Examination of ANT and cSCC tissue sections using immunofluorescence and immunohistochemistry showed differential, and reverse, expression of E-cadherin and vimentin among cells within an individual tumor. Collectively, our data support a hypothesis that cSCC tumors are undergoing a hybrid EMT program, where there is variation in expression of EMT markers by cells within a tumor mass that may be facilitating invasion. This hybrid EMT program may be promoting both survival and invasiveness of the tumors. A better understanding of this hybrid EMT process may influence therapeutic strategies in more invasive disease. Citation Format: Christopher S. Pulford, Chandana K. Uppalapati, McKale R. Montgomery, Elizabeth E. Hull, Kathryn J. Leyva. A hybrid epithelial to mesenchymal transition in ex-vivo cutaneous squamous cell carcinoma tissues [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr LB022.
Abstract 5223: Pediatric cancer incidence among racial/ethnic groups living in rural/urban areas of the United States
Authors: Priya B. Shetty, Philip J. Lupo, Michael E. Scheurer
Journal: Cancer Research (2022)

Abstract Background: The impact of urban/rural residence on pediatric cancer incidence has not been well studied. Additionally, the impact of race/ethnicity on pediatric cancer incidence by urban/rural status has not been evaluated, which could inform our understanding of the roles of shared genetic and environmental causes of these malignancies. Methods: Using SEER18, we calculated pediatric cancer incidences for individuals diagnosed 2000-2018 by residence (urban/rural). Next we calculated incidence rate ratios (IRR) to evaluate the role of race/ethnicity on incidence stratified by urban vs. rural status. Results: See Table. Overall, most incidences were similar by residence, i.e., lower or equal in rural versus urban areas, except the rural group having significantly lower incidences of leukemias and germ cell tumors (GCTs). Additionally, the incidence of most pediatric cancers was consistently higher among NHW in both urban and rural areas. Yet, incidence of some cancers differed by urban/rural residence within race/ethnicity: retinoblastoma (NHB, Hispanic, and API); soft tissue sarcomas (NHB and AI/AN); hepatic tumors (AI/AN); and GCTs (API). Conclusions: In general, Hispanic, NHB, and AI/AN populations have similar incidence of pediatric cancers in urban or rural areas. These groups have some shared bio-geographical ancestry, suggesting a possible effect of genetics on risk. Further, differences in incidence by urban/rural residence within race/ethnicity suggest a possible role of environment for some cancers. Interestingly, for GCTs, NHB had a lower IRR in urban and rural areas, but Hispanic populations had a significantly higher IRR. This finding, consistent with a recent study in adults, suggest that African ancestry may confer a protective effect on risk of GCTs. Further, the GCT effect sizes were more protective in the rural group for each race/ethnicity group, suggesting the possible role of environmental factors and interactions of environment with ancestry. Pediatric cancer incidence by race/ethnicity group and urban/rural residence Citation Format: Priya B. Shetty, Philip J. Lupo, Michael E. Scheurer. Pediatric cancer incidence among racial/ethnic groups living in rural/urban areas of the United States [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5223.
Abstract 2634: Vasoactive intestinal polypeptide (VIP) regulates ZEB1 expression in cancer
Authors: Ishani H. Rao, Rohan Dhamsania, Edmund K. Waller, Sanjay Chandrasekaran
Journal: Cancer Research (2022)

Abstract Background: In cancer immunology, VIP is a neuropeptide with pleiotropic effects that include inhibiting T cell activation, increasing Treg frequency, and augmenting the myeloid-derived suppressor cells function. VIP expression by cancer may represent a paracrine immune-checkpoint pathway while simultaneously having autocrine effects on cancer growth. We used an in silico model to identify genes whose over-expression in cancer was correlated with VIP expression and confirmed the role of VIP receptor (VIPR) signaling in vitro using VIPR inhibitors. Methods: The TCGA PanCan dataset (UCSC Xena) was used to compare mRNA expression data of VIP versus 760 genes involved in 48 cancer related pathways. Associations by cancer histology and germ layer were calculated. A Pearson’s Coefficient cutoff of R &amp;gt; [0.3] defined a significant gene association. VIP and target gene expression were confirmed and quantified by western blot analysis in cancer cell lines and VIPR signaling was inhibited using ANT008, a novel VIPR inhibitor. Results: Significant associations were observed between VIP expression and 10 genes (Table 1). Strong associations (R &amp;gt; [0.4]) were observed in cancers derived from ectodermal and mesodermal germ layers. The strongest gene association was for VIP and ZEB1 in stomach adenocarcinoma (STAD, R = 0.7643). In vitro experiments using Jurkat T cells confirmed expression of VIP and ZEB1 proteins. Treatment with the VIPR inhibitor ANT008 (10μM) reduced VIP and ZEB1 protein expression by 50%. A similar fold increase in ZEB1 expression was observed with exogenous VIP. PCR studies are currently underway. Conclusions: The results demonstrate autocrine signaling between VIP expression and cancer associated gene pathways. ZEB1 is a known EMT (epithelial mesenchymal transition) regulator, and our in vitro studies novelly link VIP to EMT and demonstrate that this pathway is therapeutically targetable using a VIPR inhibitor. Further studies in the pertinent tumor histologies are warranted. Table 1. Genes All Samples Ectoderm (All) Mesoderm (All) Endoderm (All) MAPK3 0.3120 0.3537 0.2252 0.3380 ZEB1 0.3621 0.4341 0.4901 0.3348 NOS2 0.3611 0.3186 0.4849 0.3428 TEK 0.3113 0.3336 0.5131 0.2600 PTCH1 0.3031 0.4040 -0.0061 0.2879 EI4G1 -0.3216 -0.4268 -0.3779 -0.2064 GMPS -0.3074 -0.4698 -0.3005 -0.0928 CDK2 -0.3186 -0.4687 -0.2345 -0.0563 RUVBL1 -0.3135 -0.3270 -0.4716 -0.1886 TIMELESS -0.3036 -0.4284 -0.3717 -0.1505 Citation Format: Ishani H. Rao, Rohan Dhamsania, Edmund K. Waller, Sanjay Chandrasekaran. Vasoactive intestinal polypeptide (VIP) regulates ZEB1 expression in cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2634.